Blood-borne metastasis is highly complex process by which tumor cell emboli successfully arrest in and penetrate the vessel wall of the microvasculature. Recent experimental evidence suggests that the invading tumor cells destroy the basement membrane of the microvascular endothelium by the elaboration of degradative enzymes. An in vitro homologous model system has been developed to examine the process of human tumor cell invasion, using microvascular endothelial cells isolated from human dermis. In contrast to endothelial cells isolated from large blood vessels, the cultured microvascular endothelial cells elaborate a subendothelial matrix that contains type IV collagen, laminin, and heparan sulfate proteoglycan, which are assembled into an ultrastructurally identifiable basal lamina. Using this in vitro system, the process of metastatic tumor cell invasion of the microvascular endothelium and associated basement membrane will be further defined. The major objectives of the proposed research are twofold; first, to examine the process by which tumor cells adhere to and invade the endothelial cell layer, and second to characterize the mechanism by which tumor cells adhere to and degrade the subendothelial basement membrane. The specific aims are: (1) To determine the biological and biochemical mechanisms for the preferential adhesion of tumor cells to the subendothelial matrix as compared with the microvascular endothelial cell surface. (2) To examine how tumor cells invade the microvascular endothelial cell monolayer by inducing retraction of adjacent endothelial cells. (3) To evaluate the potential role of platelets in promoting tumor cell adhesion to microvascular endothelium and the subendothelial basement membrane-matrix. (4) To examine the envolvement of specific proteinases in tumor cell-induced degradation of glycoproteins and type IV collagen in the microvascular basement membrane.